The pathogenesis and clinical impact of HIV associated bone loss is still unclear. We hypothesize that bone resorption is initiated in HIV infection by the upregulation of two pro-resorption cytokines (TNF-alpha and RANK Ligand) during T cell activation, and that antiretrovirals such as ritonavir, which can potentiate RANKL activity, can further exacerbate bone loss. Potential morbidity and need for intervention may be far greater in postmenopausal HIV+ women. From our pilot study of 32 HIV+ postmenopausal women, lumbar spine osteoporosis was present in 41% as compared to 22% in matched historical controls. To expand upon these findings, three separate studies are proposed: a longitudinal study with prospectively recruited HIV+ and HIV- postmenopausal women, a histomorphic study to evaluate bone remodeling in women on a ritonavir boosted regimen, and a randomized, double-blinded, placebo-controlled study to evaluate the efficacy and tolerability of once-weekly risedronate treatment in HIV+ women with low bone density (BMD). 100 HIV+ and 100 HIV- postmenopausal women matched for age and ethnicity will be recruited for a two year longitudinal study and evaluated at regular intervals with respect to BMD, gonadal and calciotropic hormones, bone turnover markers and pro-resorption cytokines. We hypothesize that prevalence of osteoporosis and rate of bone loss will be greater in the HIV+ group even after adjustment for established risk factors. Utilizing an in vitro model of osteoclastogenesis, we will also compare the ability of sera and peripheral blood mononuclear cells from these subjects to induce and undergo osteoclastogenesis. As an exploratory study, histomorphometry will be assessed in 15 postmenopausal women on Iopinvair/ritonavir and 15 ART-naive HIV+ postmenopausal women. Lastly, 50 women with T scores less than -1.5 will be randomized to once-weekly risedronate (35mg) or placebo treatment for 12 months. Efficacy will be determined by comparison of change in BMD and tolerability assessed. Mentorship and support through the K23 are essential at this stage of my training in order to develop as an independent researcher. Over the course of this award, my research experience will be augmented by a multidisciplinary mentorship, didactic studies in bone metabolism and disease, training in the performance and interpretation of bone biopsies, training in the performance of important techniques in molecular biology, and advanced coursework in Epidemiology.